Table of Contents

Title Page

Advisory Board Members

Preface

Part I: General Philosophy

Chapter 1: New Trends in Drug Discovery
1. 1.1 Introduction
2. 1.2 New Trends in NCE Discovery
3. 1.3 Enhanced Lead Generation Strategies
4. 1.4 Early Assessment of Development Aspects during Drug Discovery
5. 1.5 New Biological Entities (NBEs)
6. 1.6 General Challenges in Drug Discovery
7. 1.7 Summary
8. Acknowledgments
9. List of Abbreviations
10. References
Chapter 2: Patenting Small and Large Pharmaceutical Molecules
1. 2.1 The Role of Patents in the Pharmaceutical Industry
2. 2.2 Classification of Active Pharmaceutical Ingredient Grouping
3. 2.4 Patent Term Extensions and Adjustments, Supplementary Protection Certificates, and Data Exclusivity in Biopharmaceutics
4. 2.5 Patent Lifecycle Management
5. 2.6 Conclusion
6. List of Abbreviations
7. References

Part II: Drug Class Studies

Chapter 3: Kinase Inhibitor Drugs
1. 3.1 Introduction
2. 3.2 Historical Overview
3. 3.3 Approved Kinase Inhibitors
4. 3.4 New Directions
5. 3.5 Conclusion
6. List of Abbreviations
7. References
Chapter 4: Evolution of Nonsteroidal Androgen Receptor Antagonists
1. 4.1 Introduction
2. 4.2 Flutamide (Eulexin®)
3. 4.3 Nilutamide (Anandron®)
4. 4.4 Bicalutamide (Casodex®)
5. 4.5 Enzalutamide (Xtandi®)
6. 4.6 Outlook
7. 4.7 Conclusion
8. List of Abbreviations
9. References

Part III: Case Studies

Chapter 5: Development of T-Cell-Engaging Bispecific Antibody Blinatumomab (Blincyto®) for Treatment of B-Cell Malignancies
1. 5.1 Introduction
2. 5.2 Discussion
3. 5.3 Summary
4. List of Abbreviations
5. References
Chapter 6: Ceritinib: A Potent ALK Inhibitor for the Treatment of Crizotinib-Resistant Non-Small Cell Lung Cancer Tumors
1. 6.1 Introduction
2. 6.2 Drug Design and Strategy
3. 6.3 Synthesis of Ceritinib
4. 6.4 In Vitro Evaluation of Ceritinib
5. 6.5 In Vitro ADME Evaluation of Ceritinib
6. 6.6 Preclinical Pharmacokinetic Evaluation of Ceritinib
7. 6.7 In Vivo Evaluation of Ceritinib
8. 6.8 Evaluation of Ceritinib in Crizotinib-Resistance Mutations
9. 6.9 Mouse Model of Crizotinib-Resistant Tumors
10. 6.10 Clinical Phase I Evaluation of Ceritinib
11. 6.11 Conclusion
12. List of Abbreviations
13. References
Chapter 7: Discovery, Development, and Mechanisms of Action of the Human CD38 Antibody Daratumumab
1. 7.1 Introduction
2. 7.2 CD38: The Target
3. 7.3 Discovery of Daratumumab
4. 7.4 Daratumumab Combines Multiple Mechanism of Actions
5. 7.5 Single-Agent Antitumor Activity of Daratumumab in Multiple Myeloma
6. 7.6 Daratumumab-Based Combination Therapies in Multiple Myeloma
7. 7.7 Potential of Daratumumab Outside Multiple Myeloma
8. 7.8 Conclusions and Future Perspectives
9. 7.9 Summary
10. List of Abbreviations
11. References
Chapter 8: The Discovery of Obeticholic Acid (Ocaliva™): First-in-Class FXR Agonist
1. 8.1 Introduction
2. 8.2 Bile Acids in Health and Disease
3. 8.3 The Early Bile Acid Medicinal Chemistry Program at the University of Perugia
4. 8.4 The Breakthrough (1999): Bile Acids Are the Endogenous Ligands of the Farnesoid X Receptor (FXR)
5. 8.6 Properties and Preclinical Studies of Obeticholic Acid
6. 8.7 Obeticholic Acid (Ocaliva™) for the Treatment of Primary Biliary Cholangitis (PBC): Phases I–III Clinical Studies to Establish Clinical Efficacy
7. 8.8 Conclusions and Future Directions
8. List of Abbreviations
9. References
Chapter 9: Discovery and Development of Obinutuzumab (GAZYVA, GAZYVARO), a Glycoengineered Type II Anti-CD20 Antibody for the Treatment of Non-Hodgkin Lymphoma and Chronic Lymphocytic Leukemia
1. 9.1 Introduction
2. 9.2 Preclinical Experience with Obinutuzumab
3. 9.3 Clinical Experience with Obinutuzumab
4. 9.4 Conclusions
5. Acknowledgments
6. List of Abbreviations
7. References
Chapter 10: Omarigliptin (MARIZEV™, MK-3102)
1. 10.1 Introduction
2. 10.2 Summary
3. List of Abbreviations
4. References
Chapter 11: Opicapone, a Novel Catechol-O-Methyltranferase Inhibitor (COMT) to Manage the Symptoms of Parkinson's Disease
1. 11.1 Introduction
2. 11.2 COMT Inhibitors Used in l-DOPA Treatment
3. 11.3 The Discovery of Opicapone
4. 11.4 Opicapone Preclinical Profile
5. 11.5 Clinical Studies with Opicapone
6. 11.6 Conclusion
7. List of Abbreviations
8. References
Chapter 12: The Discovery of Osimertinib (TAGRISSO™): An Irreversible Inhibitor of Activating and T790M Resistant Forms of the Epidermal Growth Factor Receptor Tyrosine Kinase for the Treatment of Non-Small Cell Lung Cancer
1. 12.1 Introduction
2. 12.2 Discussion
3. 12.3 Summary
4. List of Abbreviations
5. Acknowledgment
6. References
Chapter 13: Discovery of Pitolisant, the First Marketed Histamine H3-Receptor Inverse Agonist/Antagonist for Treating Narcolepsy*
1. 13.1 Introduction
2. 13.2 Chemical Background
3. 13.3 Generation of a Chemical Lead
4. 13.4 Pharmacological Screening Methods
5. 13.5 Structure–Activity Optimization
6. 13.6 Generation of Pitolisant
7. 13.7 Preclinical Development Studies
8. 13.8 Clinical Development Studies
9. 13.9 Conclusion
10. Acknowledgment
11. List of Abbreviations
12. References
Chapter 14: Discovery and Development of Safinamide, a New Drug for the Treatment of Parkinson's Disease
1. 14.1 Introduction
2. 14.2 Discovery of Safinamide
3. 14.3 Mechanisms of Action of Safinamide
4. 14.4 Preclinical In Vivo Pharmacological Characterization of Safinamide
5. 14.5 Pharmacokinetics and Metabolism (PKM)
6. 14.6 Clinical Efficacy of Safinamide
7. 14.7 Safety and Tolerability in Clinical Studies
8. 14.8 Summary of Clinical Trials and Marketing Authorization
9. 14.9 Conclusion
10. List of Abbreviations
11. References
Chapter 15: Discovery and Development of Trifluridine/Tipiracil (Lonsurf ™)
1. 15.1 Introduction
2. 15.2 A Concept to Maximize the Antitumor Effect of 5-FU
3. 15.3 A Concept to Maximize the Antitumor Effect of FTD
4. 15.4 The Mechanism Underlying the Antitumor Effect of Trifluridine
5. 15.5 Characterization of the Pharmacologic Effect of FTD/TPI
6. 15.6 Clinical Pharmacology and Determination of the Optimal Dosing Scheme of FTD/TPI
7. 15.7 Clinical Efficacy, Safety, and Approval
8. 15.8 Summary
9. List of Abbreviations
10. References
Index

End User License Agreement

List of Illustrations

Chapter 1: New Trends in Drug Discovery

Figure 1.1 Structures of osimertinib, lumacaftor, ivacaftor and palbociclib.
Figure 1.2 Structures of thalidomide and lenalidomide.
Figure 1.3 X-Ray structure of EGFR kinase (a) and afatinib in binding site of EGFR kinase (b).
Figure 1.4 Structure of fingolimod.
Figure 1.5 Structure of dabigatran.
Figure 1.6 Structure of tirofiban.
Figure 1.7 Structure of vemurafenib.
Figure 1.8 Structure of nintedanib.
Figure 1.9 Different purposes and requirements for probes and drugs.
Figure 1.10 Cumulative success rate from phase I to launch.
Figure 1.11 Modular composition of ADCs.
Figure 1.12 Bispecific antibody formats.

Chapter 3: Kinase Inhibitor Drugs

Figure 3.1 The number of approved kinase inhibitor drugs over the last 2 decades.
Figure 3.2 Structural features of a typical protein kinase and classification of inhibitor binding modes. (a) General structural features of kinases (PDB ID: 4RRV).
Figure 3.3 Chronological summary of the discovery history of kinase inhibitors and related key events.
Figure 3.4 Prototype kinase inhibitors.
Figure 3.5 FDA-approved non-covalent small molecule kinase inhibitors (Part I).
Figure 3.6 FDA-approved non-covalent small molecule kinase inhibitors (Part II).
Figure 3.7 FDA-approved non-covalent small molecule kinase inhibitors (Part III).
Figure 3.8 FDA-approved covalent small molecule kinase inhibitors.
Figure 3.9 FDA-approved rapalogs.
Figure 3.10 Approved ROCK kinase inhibitors by the Japanese Ministry of Health.
Figure 3.11 Approved kinase inhibitors in China (icotinib) and South Korea (radotinib).

Chapter 4: Evolution of Nonsteroidal Androgen Receptor Antagonists

Figure 4.1 Androgen receptor antagonists.
Figure 4.2 Flutamide and its active metabolite hydroxyflutamide.
Figure 4.3 Hydroxyflutamide conformation that inspired the hydantoin of nilutamide.
Figure 4.4 SAR of bicalutamide.
Figure 4.5 The active enantiomer of bicalutamide.
Figure 4.6 The path to enzalutamide.
Figure 4.7 Anti-androgens in clinical phase III.

Chapter 5: Development of T-Cell-Engaging Bispecific Antibody Blinatumomab (Blincyto®) for Treatment of B-Cell Malignancies

Figure 5.1 The principle of redirected target cell lysis by immune cells engaged via antibodies. Left: engagement of a natural killer (NK) cell by a regular human IgG1 monoclonal antibody is shown. The antibody connects target and NK cells through simultaneous bispecific binding to Fcγ receptor and target antigen. This will trigger the NK cell to release its toxic payload, which is stored inside granules, onto target cells. This process is called antibody-dependent cellular cytotoxicity (ADCC) and contributes to the therapeutic potential of many commercial monoclonal antibodies of the human IgG1 isotype. Right: engagement of a cytotoxic T cell by a bispecific antibody construct is shown. Naturally, ADCC is not possible with regular T cells because they lack Fcγ receptors for antibody binding. Bispecific T-cell-engaging antibody constructs typically bind to the CD3ϵ subunit of the T-cell receptor (TCR) complex, which allows for highly effective activation of T cells and release of toxins. Of note, bispecific antibody constructs, like blinatumomab, can use the same target antigens as monoclonal antibodies. T cells are thought to have a much higher cytotoxic potential than NK cells, which translates into far lower doses needed for therapy.
Figure 5.2 Construction and structure of blinatumomab. Blinatumomab is derived from the variable antigen-binding domains (V_H/V_L) of two monoclonal antibodies, one specific for CD19 on B target cells (left, red) and the other specific for CD3ϵ on T cells (right, green). The four V_H and V_L immunoglobulin domains are recombinantly linked by three glycine–serine linker sequences (arrows) as shown in the middle, which aligns the four domains on a single polypeptide chain of approximately 50 kDa. Of note, blinatumomab has only a third of the size of a regular monoclonal antibody. It lacks the Fcγ domain, which comes with better tissue penetration but a dramatically reduced serum half-life. The position of a hexahistidine sequence (His-tag) at the C-terminus (C) is shown. It is used for affinity purification and detection of blinatumomab in various assays. Equilibrium dissociation constants (K_D) are given for the CD19 (N-terminal) and CD3 binding domain (C-terminal), respectively.
Figure 5.3 Mode of action of blinatumomab. Via bispecific binding to CD19 and CD3, blinatumomab can transiently connect a target cell (left) with a cytotoxic T cell (right). This will result in the formation of a so-called immunological cytolytic synapse between T and target cell. The synapse sends a strong activation signal into the T cell, triggering the fusion of cytotoxic granules with the T-cell membrane and release of granzymes and perforin into the synaptic cleft (large arrow). Perforin will insert into the target cell membrane and granzymes get delivered into the cytoplasm of target cells. As a consequence, target cells get killed by activated caspases and pores formed by perforin in their cell membrane. The reactions shown in italics have been observed during target cell lysis by blinatumomab. PARP is poly-ADP-ribose polymerase that gets cleaved by activated caspases. While target cells die, T cells get strongly activated (left, red). For instance, they start proliferating, produce new toxins, and eventually adopt a serial killing mode.

Chapter 6: Ceritinib: A Potent ALK Inhibitor for the Treatment of Crizotinib-Resistant Non-Small Cell Lung Cancer Tumors

Figure 6.1 Selected examples of ALKi.
Figure 6.2 Hypothesized mechanism of the reactive adducts formation from 1 and 9.
Figure 6.3 Drug design of ceritinib.
Figure 6.4 Activity of LDK378 in a mouse H2228 (a) and Karpas299 (b) mouse xenografts.
Figure 6.5 Long-term efficacy of ceritinib in WT H2228 mouse xenograft model.
Figure 6.6 Crystal structure of LDK378 bound to ALK and position of selected crizotinib-resistance mutations.
Figure 6.7 In vivo evaluation of ceritinib in C1156Y (a) and I1171T (b) crizotinib-resistant mouse xenograft models.
Figure 6.8 Tumor response of ceritinib in ALK+ patients (Ph I study).
Figure 6.9 Typical patient response to ceritinib. The Figure shows positron-emission tomographic scan before (a) and after (b) 3.5 weeks of ceritinib treatment at a dose of 400 mg.
Scheme 6.1 Synthesis of LDK378 (1, ceritinib). Reagents and conditions: (a) propane-2-thiol, K₂CO₃, DMF, 45 °C ON. (b) NaBO₃, AcOH, 60 °C. (c) H₂/Pd/C, EtOAc/MeOH (10/1). (d) NaH, DMF/DMSO, 0–20 °C. (e) KNO₃, H₂SO₄, 0–20 °C. (f) IPA, Cs₂CO₃, 60 °C, 24 h. (g) 4-Pyridineboronic acid, 1-BuOH (Pd₂(dba)₃, 2-dicyclohexylphosphine-2′-6′-dimethoxy biphenyl, MW, 150 °C. (h) AcOH/TFA; PtO₂, H₂, RT, 3 h. (i) Anh. HCl-dioxane, 0.1 M anh. 2-methoxy ethanol, 135 °C, 2 h.

Chapter 7: Discovery, Development, and Mechanisms of Action of the Human CD38 Antibody Daratumumab

Figure 7.1 Broad-spectrum tumor cell killing mechanisms of daratumumab.

Chapter 8: The Discovery of Obeticholic Acid (Ocaliva™): First-in-Class FXR Agonist

Figure 8.1 Ocaliva structure, dosage, and indications.
Figure 8.2 (a) General structure of C24 and C27 bile acids. (b) Steric representation of the cis and trans A/B junction of bile acids. (c) Cooperative formation of hydrogen bonds in the hydrophilic area of bile acids and hydrophobic/hydrophilic faces responsible for micelle formation.
Figure 8.3 Biosynthesis, enterohepatic circulation, and metabolism of bile acids in humans.
Figure 8.4 Body and side chain modified UDCA analogues.
Figure 8.5 Biliary secretion rate of the 6-MUDCA (8) and its hepatic metabolites in bile fistula hamster after IV and ID administration at a dose of 10 µmol⁻¹·min⁻¹ kg⁻¹. (
Figure 8.6 Biliary secretion of (a) lactate dehydrogenase and (b) alkaline phosphatase in bile fistula rats during ID saline (▪), UDCA (▴), or 6-FUDCA (•) administration at a dose of 8 µmol·min⁻¹ kg⁻¹ and simultaneous IV infusion of TCDCA at the same dose. (
Figure 8.7 (a) Substrate specificity for bacterial 7-dehydroxylase on the four cyclopropyl isomers in respect to UDCA. (b) Kinetics of biliary excretion of the four isomers of CUDCA. Left panel refers to the unconjugated form, compared with UDCA. Right panel, BA administered as taurine conjugates in comparison with TUDCA. (
Figure 8.8 Activation of FXR by naturally occurring cholesterol metabolites. Full-length human (filled bars) and full-length murine (open bars) FXR were performed with extracts of CV-1 cells transfected with expression plasmids for human or murine FXR. Cells were treated with 100 µM of the indicated bile acids or farnesol or 10 µM of TTNPB.
Figure 8.9 FXR-mediated genomic actions of bile acids. (a) FXR activation regulates bile acid enterohepatic recycling and detoxification. Genes whose expression is directly induced by bile acids and FXR are in purple; those in yellow are inhibited by bile acids. (b) Mechanism of regulation of lipid and bile acid homeostasis by bile acids. On the one hand, SREBP1-c and CYP7A1 expressions are elevated by oxysterol-induced LXR activation, which increases triglyceride and bile acid biosynthesis. FXR-mediated induction of SHP, on the other hand, interferes with the activity of LXR to induce SREBP1-c and CYP7A1 and so inhibits lipogenesis and BA synthesis. In addition, FXR-mediated induction of intestinal mouse FGF15 is an alternative SHP-independent signal from the gut to the liver to inhibit bile acid biosynthesis. (c) Transhepatic flux of BAs. Low transhepatic BA flux is observed during fasting or inter-prandial periods or due to medical manipulation of the bile acid pool (e.g., bile acid sequestrants or ileal exclusion). Low BA flux coincides with a decrease in serum low-density lipoprotein (LDL) cholesterol levels and an increase in triglyceride (TG)-enriched lipoproteins (very low-density lipoprotein; VLDL) and high-density lipoprotein (HDL) cholesterol linked to a reduced activation of the FXR-signaling pathway. (d) A high transhepatic bile acid flux induces FXR activity, which correlates with a rise in serum LDL cholesterol level and a fall in VLDL and HDL.
Figure 8.10 Representative examples of bile acid derivatives, naturally occurring and synthetic compounds discovered as FXR ligands.
Figure 8.11 Overall view of the crystal rFXR complexed with obeticholic acid (1) (chain A): H12 is shown in purple, GRIP-1 peptides in red, and obeticholic acid (1) in green.
Figure 8.12 Superposition of crystal structures of obeticholic acid (1) (shown in green) pointing out the FXR activation switch.
Figure 8.13 Comparison of the chain a and b complexes in the asymmetric unit of the OCA structure. H12 surface is shown in purple, the peptide in the primary coactivator groove is shown in red, and the second peptide seen in the chain B complex (of both 1OSV and 1OT7 crystals) is shown in green.
Figure 8.14 Hydrophobic pocket of in the FXR ligand binding domain accommodating the ethyl group at the C6 alpha position of OCA.
Figure 8.15 Structural and physicochemical complementarity between bile acid scaffold and the FXR ligand binding domain. (
Figure 8.16 (a) Biliary secretion and pharmacokinetics of OCA (1) and their respective metabolites after intravenous (Δ) and intraduodenal (○) administration. (b) Plasma concentration of OCA (1) and their metabolites after intraduodenal administration. (
Figure 8.17 Five-day administration of OCA (1) protects against changes in basal flow induced by E₂17α.
Figure 8.18 Effect of infusion of LCA alone (open circle) or in combination with OCA (1) (filled circle) on bile flow.
Figure 8.19 FXR activation by OCA (1) exerts beneficial effect in NASH through regulation of gluconeogenesis and glycogenolysis in the liver, regulation of peripheral insulin sensitivity in striated muscle and adipose tissue, increased lipid storage in adipocytes, and upregulation of FGF15/19 production.
Figure 8.20 Discovery of potent and selective FXR and TGR5 bile acid-based agonists.
Scheme 8.1 Scale-up synthesis of OCA (1). (A) First synthesis: reagents and conditions: (a) pTSA, 3,4-dihydro-2H-pyrane, dioxane, r.t.; (b) i. LDA, EtBr, THF, −78 °C; ii. HCl, MeOH, r.t.; (c) NaBH₄, MeOH; (d) NaOH, MeOH, r.t.. (B) Optimized synthesis: reagents and conditions: (e) LDA, TMSCl, Et₃N, THF, −78 °C; (f) MeCHO, BF₃-Et₂O, −60; (g) i. H₂, Pd, MeOH; ii. KOH, MeOH; (h) NaBH₄, THF/MeOH.

Chapter 9: Discovery and Development of Obinutuzumab (GAZYVA, GAZYVARO), a Glycoengineered Type II Anti-CD20 Antibody for the Treatment of Non-Hodgkin Lymphoma and Chronic Lymphocytic Leukemia

Figure 9.1 Putative mechanisms of action of obinutuzumab. ADCC, antibody-dependent cell-mediated cytotoxicity; ADCP, antibody-dependent cellular phagocytosis; CDC, complement-dependent cytotoxicity.
Figure 9.2 Key clinical studies of obinutuzumab in B-cell lymphoma. 1°, primary; 1L, first line; B, bendamustine; BOR, best overall response; chemo, chemotherapy; CHOP, cyclophosphamide, doxorubicin, vincristine, and prednisone; Clb, chlorambucil; CLL, chronic lymphocytic lymphoma; CR, complete response; DLBCL, diffuse large B-cell lymphoma; DLT, dose-limiting toxicity; FC, fludarabine and cyclophosphamide; FL, follicular lymphoma; G, obinutuzumab; iNHL, indolent non-Hodgkin lymphoma; IRR, infusion-related reaction; mono, monotherapy; NHL, non-Hodgkin lymphoma; ORR, overall response rate; PFS, progression-free survival; Ph, phase; R, rituximab; R/R, relapsed/refractory.

Chapter 10: Omarigliptin (MARIZEV™, MK-3102)

Figure 10.1 Marketed DPP-4 inhibitors for the treatment of T2DM.
Figure 10.2 The superposition of sitagliptin and a cyclohexylamine analogue in the DPP-4 active site using their co-crystal structures of DPP-4 (PDB codes: 1X70 and 2P8S). The image was generated using PyMol.
Figure 10.3 Lead optimization leading to omarigliptin (8).
Figure 10.4 The superposition of sitagliptin and fluoro-omarigliptin in the DPP-4 active site using their co-crystal structures of DPP-4 (PDB codes: 1X70 and 4PNZ). The image was generated using PyMol.
Figure 10.5 Results with omarigliptin in the oral glucose tolerance test. Omarigliptin was administered orally 1 h prior to dextrose challenge. Results were recorded as change in plasma glucose excursion (AUC).
Figure 10.6 Percent change from baseline in HbA1c (99.5% CI) of T2DM patients after 12 weeks of omarigliptin (once weekly).
Figure 10.7 Percent change from baseline in HbA1c (99.5% CI) of T2DM patients after a 66-week extension study. Placebo patients from base study were switched to metformin (started at 500 mg q.d. and up-titrated to 1000 mg b.i.d.). Patients from base study taking various once-weekly doses of omarigliptin 0.25, 1, 3, 10, and 25 mg were switched to 25 mg omarigliptin, given once weekly.
Schemes 10.1 Synthesis of methylsulfonylpyrrolopyrazole intermediate 14.
Scheme 10.2 Synthesis of tetrahydropyranone intermediate 22.
Scheme 10.3 Synthesis of omarigliptin.
Scheme 10.4 Improved diastereoselective synthesis of intermediate 22.
Scheme 10.5 Manufacturing synthesis of omarigliptin.

Chapter 11: Opicapone, a Novel Catechol-O-Methyltranferase Inhibitor (COMT) to Manage the Symptoms of Parkinson's Disease

Figure 11.1 Chemical structures of tolcapone 1, entacapone 2, and nebicapone 3.
Figure 11.2 Chemical structure of screening hit BIA 9-693 (4a).

Chapter 12: The Discovery of Osimertinib (TAGRISSO™): An Irreversible Inhibitor of Activating and T790M Resistant Forms of the Epidermal Growth Factor Receptor Tyrosine Kinase for the Treatment of Non-Small Cell Lung Cancer

Figure 12.1 The EGFR signaling cascade.
Figure 12.2 Anilinoquinazoline-based EGFR inhibitors.
Figure 12.3 Structure of EGFR kinase domain (pdb code 2ITY) showing the locations of activating mutations L858 (green carbon atoms) and exon 19 (purple) as well as the gatekeeper residue T790 (orange).
Figure 12.4 (a) ATP K_M (blue) and gefitinib K_d (red) values for wild-type and mutated forms of EGFR. (b) The impact of these combined effects on the apparent K_i at 1 and 10 mM ATP concentrations, indicative of cellular potency.
Figure 12.5 Irreversible anilinoquinazoline-based EGFR inhibitors.
Figure 12.6 Initial screening hit and lead compounds.
Figure 12.7 Crystal structure of 8 (green carbon atoms) bound to wild-type EGFR (pdb code 4LI5 [15]). T790 carbon atoms are shown in orange, while C797 atoms are in purple.
Figure 12.8 Inhibitors with the basic substituent on the para position of the phenyl ring.
Figure 12.9 Indole-substituted inhibitors assessed for IGF1R and hERG selectivity.
Figure 12.10 Crystal structure of 15 (green carbon atoms) bound to wild-type EGFR (pdb code 4ZAU [25]). T790 carbon atoms are shown in orange, while C797 atoms are in purple.
Figure 12.11 Tumor responses in T790M-positive patients in response to osimertinib treatment. Bars indicate complete response (red), partial response (purple), stable disease (green), and progressive disease (yellow), as well as patient who was not evaluable (blue). Data were analyzed by blinded independent central review. Evaluable for response analysis set (n = 398). Mean best percentage change in target lesion size −45%, standard deviation 28.0 (median best percentage change −47.6%; range: −100% to +90.8%) [27].

Chapter 13: Discovery of Pitolisant, the First Marketed Histamine H3-Receptor Inverse Agonist/Antagonist for Treating Narcolepsy*

Figure 13.1 Overlap in principle between agonist and antagonist binding sites.
Figure 13.2 Changes in Epworth Sleepiness Scale (ESS) score for 79 narcolepsy patients who completed 8 weeks treatment with pitolisant, modafinil, or placebo. Data points are means and error bars are SEM. During the first 7 days, all patients took a low dose (10 mg of pitolisant or 100 mg of modafinil or placebo) and then for the next 7 days a medium dose (20 mg of pitolisant or 200 mg of modafinil or placebo). On day 14 (visit 4), doses were adjusted for each patient, and patients received 10, 20 or 40 mg of pitolisant or 100, 200 or 400 mg of modafinil or placebo for the next 5 weeks. Visit 5 was on day 21, visit 6 on day 49, and visit 7 on day 56.
Scheme 13.1 Laboratory synthesis of pitolisant (FUB 649).

Chapter 14: Discovery and Development of Safinamide, a New Drug for the Treatment of Parkinson's Disease

Figure 14.1 Chemical structure of safinamide.
Figure 14.2 Chemical structure of milacemide (2-(n-pentylamino)acetamide).
Figure 14.3 Structure of milacemide analogues.
Figure 14.4 Chemical structure of α-methylmilacemide (2-(1-methylpentylamino)acetamide).
Figure 14.5 General structure of new series of milacemide analogues.
Figure 14.6 Structures of selected molecules.
Figure 14.7 In vitro and in vivo effects of safinamide on MAO enzyme activity. (a) In vitro effects on MAO-A and MAO-B in rat brain mitochondria. (b) In vitro effects on MAO-B in human platelets and brain. (c) Time-dependent effect on MAO-B in human platelets. (d) In vivo effects on MAO-A and MAO-B after oral treatment; comparison with rasagiline.
Figure 14.8 Effect of safinamide and MK-801 versus vehicle on the rotational response to chronic L-dopa in 6-OHDA-lesioned rats. $P < 0.05 versus L-dopa on day 1; *P < 0.05 versus L-dopa on day 28.
Figure 14.9 Metabolism pathways of safinamide. Enzymes: CYP = cytochrome P450, MAO-A = monoamine oxidase A, ALDH = aldehyde dehydrogenases, UGT = UDP-glucuronosyltransferases. Gluc = acyl glucuronide.
Scheme 14.1 Proposed metabolic conversion of milacemide into glycine.

Chapter 15: Discovery and Development of Trifluridine/Tipiracil (Lonsurf ™)

Figure 15.1 Structure of Lonsurf^™ (trifluridine/tipiracil).
Figure 15.2 Intracellular conversion of 5-FU leads to active metabolites.
Figure 15.3 Structure of FTC-092.
Figure 15.4 Pharmacokinetic analysis of FTD/TPI. (a) Plasma FTD levels in monkeys following an oral dose of FTD (10 mg kg⁻¹) alone or in combination with TPI at different molar ratios, as indicated.
Figure 15.5 Relationship between C_max of FTD and various ratios of TPI and FTD.
Figure 15.6 In vivo analysis of FTD accumulation and activity in xenograft models. FTD was administered by daily oral administration or continuous infusion for 14 days to mice subcutaneously implanted with human breast cancer MX-1. (a) Growth curve of xenografts. The tumor volume was measured twice a week and values indicate the means ± SD of the RTV (n = 6–7). (b) The amount of FTD incorporated into DNA extracted from MX-1 was measured using HPLC analysis. Tumor for analysis of FTD accumulation was corrected at day 7. The values indicate the means ± SD (n = 3). (c) The dUMP levels extracted from MX-1 were also measured using HPLC analysis. FTD was administered by oral administration at 0 h or continuous infusion from 0 to 24 h. FTD, trifluridine; dUMP, deoxyuridine monophosphate.
Figure 15.7 Relationship between the antitumor activity of trifluridine/tipiracil and the amount of FTD incorporated into DNA. The amount of FTD incorporated into DNA in each tumor sample is plotted on the horizontal axis, and the IRs of each antitumor study is plotted on the vertical axis. A positive correlation was observed between the amount of FTD incorporated into the DNA of tumor cells and the antitumor effect of trifluridine/tipiracil (Pearson correlation coefficient r = 0.92, R₂ = 0.84, P = 0.0013). FTD, trifluridine; IRs, inhibition rates.
Figure 15.8 Kaplan–Meier curves for overall survival (RECOURSE study). The median overall survival was 7.1 months in the TAS-102 group (vertical red dashed line) and 5.3 months in the placebo group (vertical black dashed line).

List of Tables

Chapter 1: New Trends in Drug Discovery

Table 1.1 FDA 2015 approvals with therapeutic breakthrough designation
Table 1.2 Biophysical methods for analysis of protein–ligand interactions
Table 1.3 Examples of successful hit/lead generation per strategy
Table 1.4 NBE FDA approvals in 2015
Table 1.5 Examples of successful hit/lead generation per strategy

Chapter 2: Patenting Small and Large Pharmaceutical Molecules

Table 2.1 Different classes of active pharmaceutical molecules and examples
Table 2.2 Selection invention explained on the example of Olanzapine. Left: Olanzapine as patented; Right: General version of Olanzapine which was already in the prior art
Table 2.3 Overview of monopoly rights and exclusivity privileges as discussed in the text
Table 2.4 Overview of exclusivity privileges as discussed in the text

Chapter 3: Kinase Inhibitor Drugs

Table 3.1 Targets of approved kinase inhibitor drugs

Chapter 4: Evolution of Nonsteroidal Androgen Receptor Antagonists

Table 4.1 Side effects of LHRH antagonist alone and in combination with flutamide

Chapter 6: Ceritinib: A Potent ALK Inhibitor for the Treatment of Crizotinib-Resistant Non-Small Cell Lung Cancer Tumors

Table 6.1 Activity of ceritinib in various ALK-dependent cell lines
Table 6.2 Enzymatic selectivity evaluation of ceritinib (nM)
Table 6.3 Cellular selectivity evaluation of ceritinib (nM)
Table 6.4 Profile of ceritinib
Table 6.5 Mouse, rat, dog, and monkey PK parameters of ceritinib
Table 6.6 Activity of ceritinib across a panel of major resistance mutation to crizotinib
Table 6.7 Response rate in patients with ALK+ NSCLC with ceritinib at doses 400–750 mg d⁻¹ (n = 114) from Ph I study
Table 6.8 Clinical trials ongoing with ceritinib

Chapter 7: Discovery, Development, and Mechanisms of Action of the Human CD38 Antibody Daratumumab

Table 7.1 Results of completed clinical studies with daratumumab in relapsed/refractory multiple myeloma
Table 7.2 Selected ongoing clinical studies with daratumumab in multiple myeloma and related diseases
Table 7.3 Clinical studies with daratumumab in indications outside multiple myeloma

Chapter 8: The Discovery of Obeticholic Acid (Ocaliva™): First-in-Class FXR Agonist

Table 8.1 Structure and physicochemical properties of human bile acids
Table 8.2 Bile acids receptors and target of action
Table 8.3 Potency of natural bile acids for binding FXR.^a
Table 8.4 Genes transcriptionally regulated by FXR or FXR-SHP [73]
Table 8.5 FXR ligands currently in clinical trials
Table 8.6 Potency and efficacy of C6α-modified bile acids for binding FXR.^a
Table 8.7 Physicochemical properties in aqueous solution of OCA (1), CDCA (2), and CA (4)

Chapter 9: Discovery and Development of Obinutuzumab (GAZYVA, GAZYVARO), a Glycoengineered Type II Anti-CD20 Antibody for the Treatment of Non-Hodgkin Lymphoma and Chronic Lymphocytic Leukemia

Table 9.1 Characteristics of type I and type II CD20 antibodies
Table 9.2 Key phase I and II clinical studies with obinutuzumab
Table 9.3 Phase III clinical studies with obinutuzumab

Chapter 10: Omarigliptin (MARIZEV™, MK-3102)

Table 10.1 SAR of right-hand aryltetrahydropyrrolidine moiety
Table 10.2 Eight stereoisomers of compound 7b
Table 10.3 In vivo pharmacokinetic parameters of compounds 7b and omarigliptin (8)
Table 10.4 Mean unbound percentage of omarigliptin in plasma from various species
Table 10.5 Key physicochemical properties of omarigliptin
Table 10.6 Key clinical trials for omarigliptin in type 2 diabetes mellitus
Table 10.7 Results of omarigliptin versus glimepiride in combination with metformin (95% CI)
Table 10.8 Results of omarigliptin in combination with glimepiride and metformin versus glimepiride and metformin (95% CI)
Table 10.9 Results of omarigliptin versus sitagliptin in combination with metformin (95% CI)

Chapter 11: Opicapone, a Novel Catechol-O-Methyltranferase Inhibitor (COMT) to Manage the Symptoms of Parkinson's Disease

Table 11.1 In vitro COMT inhibition by pyrazoles 4a–p in rat liver homogenates
Table 11.2 In vivo COMT inhibition by selected heterocyclic analogues in mouse liver homogenates following oral administration
Table 11.3 In vivo COMT inhibition of oxadiazoles 9, 10, and 11a in homogenates of mouse liver and brain following oral administration
Table 11.4 In vivo COMT inhibition in mice liver homogenates following oral administration and cell viability count for selected oxadiazoles
Table 11.5 In vivo COMT inhibition in rat liver homogenates following oral administration and cell viability count for selected oxadiazolyl-pyridine N-oxides

Chapter 13: Discovery of Pitolisant, the First Marketed Histamine H3-Receptor Inverse Agonist/Antagonist for Treating Narcolepsy*

Table 13.1 Pyridinyl isosteres of thioperamide
Table 13.2 Compounds where the 4(5)-substituted imidazole ring has been replaced or substituted on the ring N atom
Table 13.3 From agonist (pyridinylethylamine) to antagonist (phenbenzamine), via partial agonists, at histamine H₁ receptors
Table 13.4 A conceptual construction from agonist (histamine) to antagonist (cimetidine), via partial agonists, at histamine H₂ receptors
Table 13.5 N^α-(4-Phenylbutyl)histamine [26] provides the lead for a non-imidazole H₃-receptor antagonist
Table 13.6 H₃-Receptor antagonist activities of the phenoxy-pentanylpyrrolidines (and two other amines) with ED₅₀'s in the range 1–3 mg kg⁻¹ [31]
Table 13.7 H₃-Receptor antagonist activities of the most potent reoptimized structures
Table 13.8 Comparison of H₃-receptor antagonist potencies of imidazole compounds and the corresponding piperidine analogues
Table 13.9 Bioassay results for pitolisant (BF 2.649, FUB 649) [42, 44]

Chapter 14: Discovery and Development of Safinamide, a New Drug for the Treatment of Parkinson's Disease

Table 14.1 IC₅₀ values for the inhibition of MAO-B from ox liver mitochondria and MAO-A from rat liver mitochondria by milacemide (1) and its analogues
Table 14.2 Anticonvulsant activities of the aminoacetamide derivatives
Table 14.3 SAR of anticonvulsant activities of the α-aminoamide derivatives
Table 14.4 Pharmacological data for selected compounds versus reference standards (mice, mg kg⁻¹; p.o.)^a

Chapter 15: Discovery and Development of Trifluridine/Tipiracil (Lonsurf ™)

Table 15.1 Pyrimidine nucleoside antimetabolites used in cancer treatment
Table 15.2 Pyrimidine 2′-deoxyribonucleosides examined in combination with acyclouridine, classical thymidine phosphorylase inhibitors
Table 15.3 Inhibitory effect of 6-substituted 5-chlorouracils on human TP and rat UP
Table 15.4 Effect of 5-substitution on TP inhibitory activity of 6A5CU derivatives
Table 15.5 SAR of 5-substituted uracil derivatives for TP and UP inhibitory activity
Table 15.6 Pharmacokinetic parameters of potent, selective 5-substituted uracil derivatives.
Table 15.7 Anticancer activity against human colorectal cancer cell line CO-3 of various molar ratios of FTD and TPI in a mouse xenograft model

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Preface

The third volume of Successful Drug Discovery has a structural similarity to the first volume consisting of three parts: General Aspects, Drug Class Studies, and Case Histories. The book series supported by the International Union of Pure and Applied Chemistry (IUPAC) focuses on new drug discoveries. This volume investigates drug discoveries of the last years, that is, small-molecule drugs and biologics approved between 2013 and 2016. The book therefore contains both medicinal chemistry and biological drug research with a concept to bring these two disciplines closer to each other.

The editors thank the advisory board members – Kazumi Kondo (Otsuka, Japan) and Barry V.L. Potter (Oxford University, UK) – and the following reviewers who helped both the authors and the editors: Jim Barrow, Mark S. Cragg, Doriano Fabbro, Duke Fitch, Burkhard Fugmann, Jagath Reddy Junutula, Béla Kiss, Paul Leeson, John McCall, Carlo De Micheli, Jens-Uwe Peters, John Proudfoot, Chack Ramesha, Mathias Rask-Andersen, Jörg Senn-Bilfinger, Steve Staben, Ronald P. Taylor, Klaus T. Wanner, Scott Wolkenberg, Jay Wrobel, and Takayuki Yoshino. Special thanks are due to Ron Weir for his review from the viewpoints of the IUPAC Interdivisional Committee on Terminology, Nomenclature and Symbols (ICTNS).

Part I: General Aspects

Gerd Schnorrenberg gives an overview in the introductory chapter “New Trends in Drug Discovery” on the changing status of new drug discoveries in which besides small-molecule drugs, an increasing role of biopharmaceutical drugs can be observed.

Ulrich Storz and coworkers summarize important information in their chapter “Patenting Small and Large Pharmaceutical Molecules”, which are useful for all participants of drug research, both in academia and industry.

Part II: Drug Class Studies

Peng Wu and coworker reviewed all approved “Kinase Inhibitor Drugs” whose number amounted to 38 when this article was prepared, and they represent one of the most successful fields of drug discoveries.

Arwed Clewe and coworker provide a stepwise account on how drug discoveries optimized the drug therapy of prostate cancer in their chapter “Evolution of Non-Steroidal Androgen Receptor Antagonists.”

Part III: Case Studies

1.
Blinatumomab

Patrick A. Baeuerle describes the history, design, and development of blinatumomab, which is a new bispecific T-cell engager monoclonal antibody for the treatment of Philadelphia chromosome-negative adult patients with relapsed/refractory acute lymphoblastic leukemia.
2.
Ceritinib

Pierre-Yves Michellys reports on the discovery and development of ceritinib, a new inhibitor of anaplastic lymphoma kinase (ALK) for the treatment of ALK-positive metastatic non-small cell lung cancer.
3.
Daratumumab

Maarten L. Janmaat and coworkers have written a chapter on the discovery and development of daratumumab, which is a new monoclonal antibody for the treatment of multiple myeloma.
4.
Obeticholic acid

Roberto Pellicciari and coworkers describe how obeticholic acid, the first-in-class farnesoid X receptor (FXR) agonist, was discovered to afford a new drug for the treatment of primary biliary cholangitis. It is a good example for a successful cooperation of academia and industry in drug research.
5.
Obinutuzumab

Christian Klein and coworkers have written a chapter on the discovery and development of the type II CD20 monoclonal antibody obinutuzumab, which has been approved by Food and Drug Administration (FDA) for the treatment of chronic lymphocytic leukemia.
6.
Omarigliptin

Tesfaye Biftu has given an overview on how the long-lasting DPP-4 inhibitor omarigliptin was discovered for the once-weekly treatment of type 2 diabetes.
7.
Opicapone

László Kiss and coworkers describe the discovery and development of the very long-acting catechol-O-methyltransferase (COMT) inhibitor opicapone, which is approved by the European Medicines Agency (EMA) as adjunctive therapy for Parkinson's disease.
8.
Osimertinib

Michael J. Waring reports on a third-generation EGFR inhibitor osimertinib for the treatment of advanced non-small cell lung cancer.
9.
Pitolisant

C. Robin Ganellin and coworkers describe the history how they discovered and developed pitolisant, the first histamine H₃-receptor inverse agonist for the treatment of narcolepsy.
10.
Safinamide

Mario Varasi and coworker have written a chapter on safinamide, which was approved as an add-on therapy to L-dopa for the treatment of Parkinson's disease.
11.
Trifluridine/tipiracil

Teiji Takechi and coworkers report on the discovery and development of a new antimetabolite combination drug, in which tipiracil prevents rapid metabolism of the nucleoside analogue.

The editors and authors thank Wiley-VCH and personally Dr. Frank Weinreich for the fruitful cooperation.

János Fischer

Wayne E. Childers

Christian Klein

24 March 2017

Budapest

Philadelphia

Zurich

Magid Abou-Gharbia(Temple University, USA)	Anette Graven-Sams(Lundbeck, Denmark)
Kazumi Kondo(Otsuka, Japan)	John A. Lowe(JL3Pharma LLC, USA)
Barry V.L. Potter(Oxford University, UK)	Gerd Schnorrenberg(Boeringer Ingelheim, Germany)

Successful Drug Discovery

Volume 3

Advisory Board Members

Preface

Part I: General Aspects

Part II: Drug Class Studies

Part III: Case Studies

Part I
General Philosophy